Computational and Experimental Insights into the Mechanism of Substrate Recognition and Feedback Inhibition of Protoporphyrinogen Oxidase
作者：
Hao, Ge-Fei;Tan, Ying;Yang, Sheng-Gang;Wang, Zhi-Fang;Zhan, Chang-Guo* ;...
期刊：
PLOS ONE ,2013年8(7):e69198 ISSN：1932-6203
通讯作者：
Zhan, Chang-Guo
作者机构：
[Yang, Guang-Fu; Yang, Sheng-Gang; Tan, Ying; Wang, Zhi-Fang; Hao, Ge-Fei] Cent China Normal Univ, Coll Chem, Minist Educ, Key Lab Pesticide & Chem Biol, Wuhan, Peoples R China.;[Xi, Zhen; Tan, Ying; Wang, Zhi-Fang] Nankai Univ, State Key Lab Elementoorgan Chem, Tianjin 300071, Peoples R China.;[Zhan, Chang-Guo] Univ Kentucky, Coll Pharm, Dept Pharmaceut Sci, Lexington, KY 40536 USA.
通讯机构：
[Zhan, Chang-Guo] U;Univ Kentucky, Coll Pharm, Dept Pharmaceut Sci, Lexington, KY 40536 USA.
关键词：
Free energy;Hydrogen bonding;Oxygen;Biochemical simulations;Enzyme kinetics;Binding analysis;Enzyme inhibitors;Enzymes
摘要：
Protoporphyrinogen IX oxidase (PPO; EC 1.3.3.4) is an essential enzyme catalyzing the last common step in the pathway leading to heme and chlorophyll biosynthesis. Great interest in PPO inhibitors arises from both its significance to agriculture and medicine. However, the discovery of PPO inhibitors with ultrahigh potency and selectivity is hampered due to lack of structural and mechanistic understanding about the substrate recognition, which remains a longstanding question central in porphyrin biology. To understand the mechanism, a novel binding model of protogen (protoporphyrinogen IX, the substrate) was developed through extensive computational simulations. Subsequently, amino acid residues that are critical for protogen binding identified by computational simulations were substituted by mutagenesis. Kinetic analyses of these mutants indicated that these residues were critical for protogen binding. In addition, the calculated free energies of protogen binding with these mutants correlated well with the experimental data, indicating the reasonability of the binding model. On the basis of this novel model, the fundamental mechanism of substrate recognition was investigated by performing potential of mean force (PMF) calculations, which provided an atomic level description of conformational changes and pathway intermediates. The free energy profile revealed a feedback inhibition mechanism of proto (protoporphyrin IX, the product), which was also in agreement with experimental evidence. The novel mechanistic insights obtained from this study present a new starting point for future rational design of more efficient PPO inhibitors based on the product-bound PPO structure.
语种：
英文
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Efficient synthesis and antiproliferative activity of novel thioether-substituted flavonoids
作者：
Huang, Wei;Chen, Qiong;Yang, Wen-Chao;Yang, Guang-Fu
* （ 期刊：
European Journal of Medicinal Chemistry ,2013年66:161-170 ISSN：0223-5234
通讯作者：
Yang, Guang-Fu
作者机构：
[Yang, Guang-Fu; Yang, Wen-Chao; Huang, Wei; Chen, Qiong] Cent China Normal Univ, Coll Chem, Minist Educ, Key Lab Pesticide & Chem Biol, Wuhan 430079, Peoples R China.;[Huang, Wei] Jiangsu Simcere Pharmaceut Co Ltd, Jiangsu Key Lab Mol Targeted Antitumor Drug Res, Nanjing 210042, Jiangsu, Peoples R China.
通讯机构：
[Yang, Guang-Fu] C;Cent China Normal Univ, Coll Chem, Minist Educ, Key Lab Pesticide & Chem Biol, Wuhan 430079, Peoples R China.
关键词：
Antiproliferative activity;Chromone;Flavonoids;Microwave-assisted synthesis;Thioether
摘要：
As widely occurring natural products, flavonoids are an important source for drug discovery, due to their structural diversity and broad-spectrum biological activity. In this work, a library of novel, thioether-substituted flavonoids with diverse heterocyclic groups was synthesized via a microwave-assisted procedure with the advantages of good yields, short times, mild conditions and ready isolation of the products. Their antiproliferative activities were evaluated against six cancer cell lines, HCCLM-7, Hela, MDA-MB-435S, SW-480, Hep-2, and MCF-7 by the MU-based assay. Compared with the positive control 5-fluorouracil, three compounds, 6a, 6b and 6j were successfully identified as the most promising candidates, due to their higher potency and broad-spectrum bioactivity with IC50 values in the range of 0.43 mu M-6.7 mu M. (C) 2013 Elsevier Masson SAS. All rights reserved.
语种：
英文
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Design and synthesis of 1-(benzothiazol-5-yl)-1H-1,2,4-triazol-5-ones as protoporphyrinogen oxidase inhibitors
作者：
Zuo, Yang;Yang, Sheng-Gang;Luo, Yan-Ping;Tan, Ying;Hao, Ge-Fei;...
期刊：
Bioorganic & Medicinal Chemistry ,2013年21(11):3245-3255 ISSN：0968-0896
通讯作者：
Xi Zhen
作者机构：
[Yang, Guang-Fu; Luo, Yan-Ping; Zuo, Yang; Tan, Ying; Hao, Ge-Fei; Yang, Sheng-Gang; Wu, Qiong-You] Cent China Normal Univ, Coll Chem, Minist Educ, Key Lab Pesticide & Chem Biol, Wuhan 430079, Peoples R China.;[Xi, Zhen; Tan, Ying] Nankai Univ, State Key Lab Elementoorgan Chem, Tianjin 300071, Peoples R China.
通讯机构：
[Xi Zhen] N;Nankai Univ, State Key Lab Elementoorgan Chem, Tianjin 300071, Peoples R China.
关键词：
1,2,4-Triazol-5-one;Benzothiazole;Herbicide;Molecular design;Protoporphyrinogen oxidase
摘要：
Protoporphyrinogen oxidase (PPO, E.C. 1.3.3.4) is the action target for several structurally diverse herbicides. A series of novel 4-(difluoromethyl)-1- (6-halo-2-substituted-benzothiazol-5-yl)-3-methyl-1H-1,2,4-triazol-5(4H)-ones 2a-z were designed and synthesized via the ring-closure of two ortho-substituents. The in vitro bioassay results indicated that the 26 newly synthesized compounds exhibited good PPO inhibition effects with Ki values ranging from 0.06 to 17.79 μM. Compound 2e, ethyl 2-{[5-(4- (difluoromethyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl) -6-fluorobenzo-thiazol-2-yl]thio}acetate, was the most potent inhibitor with Ki value of 0.06 μM against mtPPO, comparable to (Ki = 0.03 μM) sulfentrazone. Further green house assays showed that compound 2f (Ki = 0.24 μM, mtPPO), ethyl 2-{[5-(4-(difluoromethyl)-3-methyl-5- oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-6-fluorobenzothiazol-2-yl]thio} propanoate, showed the most promising post-emergence herbicidal activity with broad spectrum even at concentrations as low as 37.5 g ai/ha. Soybean exhibited tolerance to compound 2f at the dosages of 150 g ai/ha, whereas they are susceptible to sulfentrazone even at 75 g ai/ha. Thus, compound 2f might be a potential candidate as a new herbicide for soybean fields. © 2013 Elsevier Ltd. All rights reserved.
语种：
英文
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Design, synthesis, and bioevaluation of benzamides: Novel acetylcholinesterase inhibitors with multi-functions on butylcholinesterase, Aβ aggregation, and β-secretase
作者：
Peng, Da-Yong;Sun, Qi;Zhu, Xiao-Lei;Lin, Hong-Yan;Chen, Qiong;...
期刊：
Bioorganic & Medicinal Chemistry ,2012年20(22):6739-6750 ISSN：0968-0896
通讯作者：
Yang, Wen-Chao
作者机构：
[Yang, Guang-Fu; Zhu, Xiao-Lei; Yang, Wen-Chao; Sun, Qi; Yu, Ning-Xi; Peng, Da-Yong; Chen, Qiong; Lin, Hong-Yan] Cent China Normal Univ, Coll Chem, Key Lab Pesticide & Chem Biol, Minist Educ, Wuhan 430079, Peoples R China.
通讯机构：
[Yang, Wen-Chao] C;Cent China Normal Univ, Coll Chem, Key Lab Pesticide & Chem Biol, Minist Educ, Wuhan 430079, Peoples R China.
关键词：
Acetylcholinesterase;Alzheimer's disease;Benzamide;Structure-based design
摘要：
Alzheimer's disease (AD) is a multifactorial syndrome with several target proteins contributing to its etiology. In this study, we conducted a structure-based design and successfully produced a series of new multi-site AChE inhibitors with a novel framework. Compound 2e, characterized by a central benzamide moiety linked to an isoquinoline at one side and acetophenone at the other, was the most potent candidate with Ki of 6.47 nM against human AChE. Particularly, it showed simultaneous inhibitory effects against BChE, Aβ aggregation, and β-secretase. We therefore conclude that compound 2e is a very promising multi-function lead for the treatment of AD. © 2012 Elsevier Ltd. All rights reserved.
语种：
英文
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Synthesis and fungicidal activity of novel pimprinine analogues
作者：
Zhang, Ming-Zhi;Chen, Qiong;Mulholland, Nick;Beattie, David;Irwin, Dianne;...
期刊：
European Journal of Medicinal Chemistry ,2012年53:283-291 ISSN：0223-5234
通讯作者：
Yang, Guang-Fu
作者机构：
[Yang, Guang-Fu; Zhang, Ming-Zhi; Chen, Qiong] Cent China Normal Univ, Coll Chem, Minist Educ, Key Lab Pesticide & Chem Biol, Wuhan 430079, Peoples R China.;[Irwin, Dianne; Clough, John; Gu, Yu-Cheng; Mulholland, Nick; Beattie, David] Syngenta, Jealotts Hill Int Res Ctr, Bracknell RG42 6EY, Berks, England.
通讯机构：
[Yang, Guang-Fu] C;Cent China Normal Univ, Coll Chem, Minist Educ, Key Lab Pesticide & Chem Biol, Wuhan 430079, Peoples R China.
关键词：
Fungicidal activity;Indole alkaloid;Pimprinine;Structure-activity relationships;Synthesis
摘要：
A simple and efficient synthetic protocol for 5-(3-indolyl)-oxazoles has been developed and further used to synthesize a series of novel analogues of natural product pimprinine. All new compounds were identified by 1H NMR, high resolution mass spectrometry, and the structures of 10 and 18o were further confirmed by X-ray crystallographic diffraction analysis. Bioassay conducted at Syngenta showed that several of the synthesized compounds exhibited fungicidal activity. Compounds 10, 17, 18h, 18o, 19h, 19i and 19l all showed effective control of three out of the seven tested phytopathogenic fungi at the highest rate screened. Compounds 17 and 19h in particular showed activity against the four pathogens screened in artificial media; Pythium dissimile, Alternaria solani, Botryotinia fuckeliana and Gibberella zeae. © 2012 Elsevier Masson SAS. All rights reserved.
语种：
英文
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Rieske Iron-Sulfur Protein of the Cytochrome bc1 Complex: A Potential Target for Fungicide Discovery
作者：
Yang, Wen-Chao;Li, Hui;Wang, Fu;Zhu, Xiao-Lei;Yang, Guang-Fu
* （ 期刊：
ChemBioChem ,2012年13(11):1542-1551 ISSN：1439-4227
通讯作者：
Yang, Guang-Fu
作者机构：
[Yang, Guang-Fu; Wang, Fu; Zhu, Xiao-Lei; Yang, Wen-Chao; Li, Hui] Cent China Normal Univ, Minist Educ, Coll Chem, Key Lab Pesticide & Chem Biol, Wuhan 430079, Peoples R China.;[Yang, Guang-Fu] Cent China Normal Univ, Minist Educ, Coll Chem, Key Lab Pesticide & Chem Biol, Luoyu Rd 152, Wuhan 430079, Peoples R China.
通讯机构：
[Yang, Guang-Fu] C;Cent China Normal Univ, Minist Educ, Coll Chem, Key Lab Pesticide & Chem Biol, Luoyu Rd 152, Wuhan 430079, Peoples R China.
关键词：
Antifungus agents;Cytochromes;Enzyme inhibitors;Rieske iron-sulfur protein
摘要：
The cytochrome bc1 complex (complex III, cyt bc1) is an essential component of cellular respiration. Cyt bc1 has three core subunits that are required for its catalytic activity: cytochrome b, cytochrome c1, and the Rieske iron-sulfur protein (ISP). Although most fungicides inhibit this enzyme by binding to the cytochrome b subunit, resistance to these fungicides has developed rapidly due to their widespread application. Resistance is mainly associated with mutations in cytochrome b, the only subunit encoded by mitochondrial DNA. Recently, the flexibility and motion of the ISP and its essential role in electron transfer have received intense attention; this leads us to propose a new classification of cyt bc1 inhibitors (three types of Qo inhibitors) that mobilize, restrict, or fix the rotation of the ISP. Importantly, the strengths of the ISP-inhibitor interactions correlate with inhibitor activity and the development of resistance to Qo inhibitors, thereby offering clues for designing novel cyt bc1 inhibitors with high potency and a low risk of resistance. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
语种：
英文
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Design, Synthesis and Fungicidal Activity of Novel Sclerotiorin Derivatives
作者：
Lin, Long;Mulholland, Nick;Huang, Shao-Wei;Beattie, David;Irwin, Dianne;...
期刊：
CHEMICAL BIOLOGY & DRUG DESIGN ,2012年80(5):682-692 ISSN：1747-0277
通讯作者：
Wu, Qiong-You
作者机构：
[Yang, Guang-Fu; Wu, Qiong-You; Huang, Shao-Wei; Lin, Long] Cent China Normal Univ, Coll Chem, Minist Educ, Key Lab Pesticide & Chem Biol, Wuhan 430079, Peoples R China.;[Irwin, Dianne; Clough, John; Gu, Yu-Cheng; Mulholland, Nick; Beattie, David] Syngenta, Jealotts Hill Int Res Ctr, Bracknell RG42 6EY, Berks, England.
通讯机构：
[Wu, Qiong-You] C;Cent China Normal Univ, Coll Chem, Minist Educ, Key Lab Pesticide & Chem Biol, Wuhan 430079, Peoples R China.
关键词：
antifungal activity;azaphilone;natural product;sclerotiorin;structural modification
摘要：
Sclerotiorin, a chlorine-containing azaphilone-type natural product, was first isolated from Penicillium sclerotiorum and has been reported to exhibit weak fungicidal activity. Optimization of the substituents at the 3- and 5-positions of the sclerotiorin framework was investigated with the aim of discovering novel fungicides with improved activity. The design of sclerotiorin analogues involved replacing the diene side chain with a phenyl group or an aromatic- or heteroaromatic-containing aliphatic side chain. The designed compounds were synthesized by cycloisomerization and subsequent oxidation of suitable 2-alkynylbenzaldehydes, in which a variety of substituents were introduced using a Sonogashira coupling reaction. The structures of these newly prepared compounds were confirmed by 1H and 13C NMR spectroscopy, HRMS and single-crystal X-ray analysis. The antifungal activity of the synthesized compounds was evaluated against seven phytopathogenic species. Compounds 3, 9g and 9h were found to have a broad spectrum of fungicidal activity, and these structurally simpler products can be recognized as lead compounds for further optimization.
语种：
英文
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Computational discovery of picomolar Q o site inhibitors of cytochrome bc 1 complex
作者：
Hao, Ge-Fei;Wang, Fu;Li, Hui;Zhu, Xiao-Lei;Yang, Wen-Chao;...
期刊：
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY ,2012年134(27):11168-11176 ISSN：0002-7863
通讯作者：
Wu, Jia-Wei
作者机构：
[Yang, Guang-Fu; Wang, Fu; Zhu, Xiao-Lei; Yang, Wen-Chao; Li, Hui; Hao, Ge-Fei] Cent China Normal Univ, Coll Chem, Minist Educ, Key Lab Pesticide & Chem Biol, Wuhan 430079, Peoples R China.;[Wu, Jia-Wei; Li, Hui] Tsinghua Univ, Sch Life Sci, Tsinghua Peking Ctr Life Sci, MOE Key Lab Prot Sci, Beijing 100084, Peoples R China.;[Huang, Li-Shar; Berry, Edward A] SUNY Upstate Med Univ, Dept Biochem & Mol Biol, Syracuse, NY 13210 USA.
通讯机构：
[Wu, Jia-Wei] T;Tsinghua Univ, Sch Life Sci, Tsinghua Peking Ctr Life Sci, MOE Key Lab Prot Sci, Beijing 100084, Peoples R China.
摘要：
A critical challenge to the fragment-based drug discovery (FBDD) is its low-throughput nature due to the necessity of biophysical method-based fragment screening. Herein, a method of pharmacophore-linked fragment virtual screening (PFVS) was successfully developed. Its application yielded the first picomolar-range Q o site inhibitors of the cytochrome bc 1 complex, an important membrane protein for drug and fungicide discovery. Compared with the original hit compound 4 (K i = 881.80 nM, porcine bc 1), the most potent compound 4f displayed 20 507-fold improved binding affinity (K i = 43.00 pM). Compound 4f was proved to be a noncompetitive inhibitor with respect to the substrate cytochrome c, but a competitive inhibitor with respect to the substrate ubiquinol. Additionally, we determined the crystal structure of compound 4e (K i = 83.00 pM) bound to the chicken bc 1 at 2.70 Å resolution, providing a molecular basis for understanding its ultrapotency. To our knowledge, this study is the first application of the FBDD method in the discovery of picomolar inhibitors of a membrane protein. This work demonstrates that the novel PFVS approach is a high-throughput drug discovery method, independent of biophysical screening techniques. © 2012 American Chemical Society.
语种：
英文
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Novel synthetic methods for N-cyano-1H-imidazole-4-carboxamides and their fungicidal activity
作者：
Yang, Wen-Chao;Li, Jing;Li, Jun;Chen, Qiong;Yang, Guang-Fu
* （ 期刊：
Bioorganic & Medicinal Chemistry Letters ,2012年22(3):1455-1458 ISSN：0960-894X
通讯作者：
Yang, Guang-Fu
作者机构：
[Yang, Guang-Fu; Li, Jun; Yang, Wen-Chao; Li, Jing; Chen, Qiong] Cent China Normal Univ, Minist Educ, Coll Chem, Key Lab Pesticide & Chem Biol, Wuhan 430079, Peoples R China.
通讯机构：
[Yang, Guang-Fu] C;Cent China Normal Univ, Minist Educ, Coll Chem, Key Lab Pesticide & Chem Biol, Wuhan 430079, Peoples R China.
关键词：
Antifungal activity;Imidazo[1,5-d][1,2,4]triazin-1(2H)-one;Imidazole;N-Cyanocarboxamide
摘要：
A novel synthetic method of N-cyanocarboxamides has been developed with advantages of mild reaction condition, simpler procedure and easy reactant-product isolation compared with the existing methods. Using this novel method, 16 new N-cyano-1H-imidazole-4-carboxamide derivatives were synthesized and their structures were characterized by spectrum analysis. Further antifungal activity study showed that most of the newly synthesized compounds have good antifungal activity selectively against Rhizoctonia solani among the six fungi tested. Particularly, compound 12h was identified as the most promising candidate with an EC 50 of 2.63 μg/mL against R. solani. © 2011 Elsevier Ltd. All rights reserved.
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英文
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治疗阿尔茨海默病的乙酰胆碱酯酶抑制剂的分子设计:从多位点抑制剂到一药多靶
作者：
杨文超;孙琦;喻宁熙;朱晓磊;杨光富
（ 期刊：
药学学报 ,2012年47(3):313-321 ISSN：0513-4870
通讯作者：
Yang, G.-F.
作者机构：
[杨光富; 杨文超; 孙琦; 喻宁熙; 朱晓磊] 华中师范大学化学学院
通讯机构：
Key Laboratory of Pesticide and Chemical Biology, College of Chemistry, Central China Normal University, China
关键词：
阿尔茨海默病;乙酰胆碱酯酶抑制剂;多位点抑制剂;一药多靶;分子设计
摘要：
阿尔茨海默病(Alzheimer’s disease,AD)是一种病因尚不明确且致病机制极为复杂的神经退行性疾病,严重威胁老年人的健康并对整个社会发展带来沉重的负担。设计开发治疗阿尔茨海默病的药物一直是药物研发领域的热点和难点,其中尤以乙酰胆碱酯酶(acetylcholinesterase,AChE)抑制剂的研究最为活跃并已在临床中成功应用。然而,现有商品化AChE抑制剂的临床治疗效果有限,并且都伴随不同程度的毒副作用。因此,寻找高效、低毒的多重结合位点的AChE抑制剂和针对多重作用靶标的多功能抑制剂(即一药多靶)成为AChE抑制剂分子设计的主要发展方向。本文结合近年来的研究进展,从代表性AChE抑制剂的化学结构和结合模式出发,对AChE抑制剂分子设计的发展历程及最新成果进行了综述。
语种：
中文
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Synthesis and Antifungal Activity of Novel Sclerotiorin Analogues
作者：
Lin, Long;Mulholland, Nick;Wu, Qiong-You;Beattie, David;Huang, Shao-Wei;...
期刊：
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY ,2012年60(18):4480-4491 ISSN：0021-8561
通讯作者：
Gu, Yu-Cheng
作者机构：
[Yang, Guang-Fu; Wu, Qiong-You; Huang, Shao-Wei; Lin, Long] Cent China Normal Univ, Coll Chem, Minist Educ, Key Lab Pesticide & Chem Biol, Wuhan 430079, Peoples R China.;[Irwin, Dianne; Clough, John; Gu, Yu-Cheng; Mulholland, Nick; Beattie, David] Syngenta Jealotts Hill Int Res Ctr, Bracknell RG42 6EY, Berks, England.
通讯机构：
[Gu, Yu-Cheng] S;Syngenta Jealotts Hill Int Res Ctr, Bracknell RG42 6EY, Berks, England.
关键词：
sclerotiorin;azaphilone;fungicides;natural product
摘要：
Sclerotiorin 1, first isolated from Penicillium sclerotiorum, has weak antifungal activity and belongs to the azaphilone-type family of natural products. Several series of sclerotiorin analogues were designed and synthesized with the aim of discovering novel fungicides with improved activity. The syntheses involved two key steps, cycloisomerization and then oxidation, and used a simple and efficient Sonogashira cross-coupling reaction to construct the required functionalized precursor. With sclerotiorin as a control, the activities of the newly synthesized analogues were evaluated against seven fungal pathogens, and several promising candidates (compounds 3a<inf>1</inf>, 3d<inf>2</inf>, 3e<inf>2</inf>, 3f<inf>2</inf> and 3k<inf>2</inf>) with greater activity and simpler structures than sclerotiorin were discovered. In addition, preliminary structure-activity relationships were studied, which revealed that not only the chlorine or bromine substituent at the 5-position of the nucleus but also the phenyl group at the 3-position and the substituent pattern on it contributed crucially to the observed antifungal activity. Analogues with a methyl substituent at the 1-position have reduced levels of activity, while those with a free hydroxyl group in place of acetoxy at the quaternary center of the bicyclic ring system retain activity. ©2012 American Chemical Society.
语种：
英文
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Structure-based methods for predicting target mutation-induced drug resistance and rational drug design to overcome the problem
作者：
Ge-Fei Hao;Guang-Fu Yang
（ ;Chang-Guo Zhan
期刊：
Drug Discovery Today ,2012年17(19-20):1121-1126 ISSN：1359-6446
通讯作者：
Yang, Guang-Fu
作者机构：
[Guang-Fu Yang; Ge-Fei Hao] Cent China Normal Univ, Coll Chem, Minist Educ, Key Lab Pesticide & Chem Biol, Wuhan 430079, Peoples R China.;[Chang-Guo Zhan] Univ Kentucky, Coll Pharm, Dept Pharmaceut Sci, Lexington, KY 40536 USA.
通讯机构：
[Yang, Guang-Fu] C;Cent China Normal Univ, Coll Chem, Minist Educ, Key Lab Pesticide & Chem Biol, Wuhan 430079, Peoples R China.
摘要：
Drug resistance has become one of the biggest challenges in drug discovery and/or development and has attracted great research interests worldwide. During the past decade, computational strategies have been developed to predict target mutation-induced drug resistance. Meanwhile, various molecular design strategies, including targeting protein backbone, targeting highly conserved residues and dual/multiple targeting, have been used to design novel inhibitors for combating the drug resistance. In this article we review recent advances in development of computational methods for target mutation-induced drug resistance prediction and strategies for rational design of novel inhibitors that could be effective against the possible drug-resistant mutants of the target. © 2012 Elsevier Ltd.
语种：
英文
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PH-responsive surface activity and solubilization with novel pyrrolidone-based gemini surfactants
作者：
Zan Jiang;Xuefeng Li;Guangfu Yang
（ ;Li Cheng;Bo Cai;...
期刊：
LANGMUIR ,2012年28(18):7174-7181 ISSN：0743-7463
通讯作者：
Dong, Jinfeng
作者机构：
[Zan Jiang; Li Cheng; Xuefeng Li; Jinfeng Dong; Bo Cai; Yi Yang] Wuhan Univ, Coll Chem & Mol Sci, Wuhan 430072, Peoples R China.;[Guangfu Yang] Huazhong Normal Univ, Minist Educ, Key Lab Pesticide & Chem Biol, Wuhan 430079, Peoples R China.
通讯机构：
[Dong, Jinfeng] W;Wuhan Univ, Coll Chem & Mol Sci, Wuhan 430072, Peoples R China.
摘要：
A new series of pH-responsive Gemini surfactants with 2-pyrrolidone head groups, N,N′-dialkyl-N,N′-di(ethyl-2-pyrrolidone)ethylenediamine (Di-C<inf>n</inf>P, where n = 6, 8 10, 12), were synthesized and characterized by <sup>1</sup>H NMR, <sup>13</sup>C NMR, ESI-MS, and elemental analysis. The surface activity and micellization behavior at acidic, neutral, and basic conditions were characterized by equilibrium surface tension and fluorescence techniques. It was found that the surface activity of Di-C<inf>n</inf>P depends on the pH of aqueous solutions due to the protonation state of surfactant molecules when pH was varied. The new compounds have lower cmc and γ<inf>cmc</inf> in comparison with that of m-2-m type conventional cationic Gemini surfactants and gluconamide-type nonionic Gemini surfactants. Fluorescence data confirm that micelles are formed when the concentration is above the cmc. Since micellization is of fundamental importance in surfactant applications such as solubilization, microemulsion, and related technologies, the significant difference in cmc at different pH of this new Gemini surfactant is employed to solubilize cyclohexane. The preliminary result indeed shows that the solubilization capacity of Di-C<inf>n</inf>P can be tuned by pH. ©2012 American Chemical Society.
语种：
英文
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Quantitative structure–activity relationships of 1,3,4-thiadiazol-2(3H)-ones and 1,3,4-oxadiazol-2(3H)-ones as human protoporphyrinogen oxidase inhibitors
作者：
Zuo, Yang;Yang, Sheng-Gang;Jiang, Li-Li;Hao, Ge-Fei;Wang, Zhi-Fang;...
期刊：
Bioorganic & Medicinal Chemistry ,2012年20(1):296-304 ISSN：0968-0896
通讯作者：
Xi, Zhen
作者机构：
[Yang, Guang-Fu; Yang, Sheng-Gang; Wu, Qiong-You; Jiang, Li-Li; Zuo, Yang; Wang, Zhi-Fang; Hao, Ge-Fei] Cent China Normal Univ, Coll Chem, Minist Educ, Key Lab Pesticide & Chem Biol, Wuhan 430079, Peoples R China.;[Xi, Zhen; Wang, Zhi-Fang] Nankai Univ, State Key Lab Elementoorgan Chem, Tianjin 300071, Peoples R China.
通讯机构：
[Xi, Zhen] N;Nankai Univ, State Key Lab Elementoorgan Chem, Tianjin 300071, Peoples R China.
关键词：
1,3,4-Oxadiazol-2(3H)-ones;1,3,4-Thiadiazol-2(3H)-ones;Human protoporphyrinogen oxidase inhibitors;Molecular docking;QSAR
摘要：
Protoporphyrinogen oxidase (Protox, EC 1.3.3.4) has attracted great interest during the last decades due to its unique biochemical characteristics and biomedical significance. As a continuation of our research work on the development of new PPO inhibitors, 23 new 1,3,4-thiadiazol-2(3H)-ones bearing benzothiazole substructure were designed and synthesized. The in vitro assay indicated that the newly synthesized compounds 1a-w displayed good inhibition activity against human PPO (hPPO) with K i values ranging from 0.04 μM to 245 μM. To the knowledge, compound 1a, O-ethyl S-(5-(5-(tert-butyl)- 2-oxo-1,3,4-thiadiazol-3(2H)-yl)-6-fluorobenzothiazol-2-yl)carbonothioate, with the K i value of 40 nM, is so far known as the most potent inhibitor against hPPO. Based on the molecular docking and modified molecular mechanics/Poisson-Boltzmann surface area (MM-PBSA) calculations, the quantitative structure-activity relationships of 1,3,4-thiadiazol-2(3H)-ones and 1,3,4-oxadiazol-2(3H)-one derivatives were established with excellent correlation relationships (r 2 = 0.81) between the calculated and experimental binding free energies. Some important insights were also concluded for guiding the future rational design of new hPPO inhibitors with improved potency. © 2011 Elsevier Ltd. All rights reserved.
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英文
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Computational simulations of structural role of the active-site W374C mutation of acetyl-coenzyme-A carboxylase: Multi-drug resistance mechanism
作者：
Xiao-Lei Zhu;Wen-Chao Yang;Ning-Xi Yu;Sheng-Gang Yang;Guang-Fu Yang
（ 期刊：
Journal of Molecular Modeling ,2011年17(3):495-503 ISSN：1610-2940
通讯作者：
Yang, Guang-Fu
作者机构：
[Guang-Fu Yang; Sheng-Gang Yang; Xiao-Lei Zhu; Wen-Chao Yang; Ning-Xi Yu] Cent China Normal Univ, Key Lab Pesticide & Chem Biol, Minist Educ, Coll Chem, Wuhan 430079, Peoples R China.
通讯机构：
[Yang, Guang-Fu] C;Cent China Normal Univ, Key Lab Pesticide & Chem Biol, Minist Educ, Coll Chem, Wuhan 430079, Peoples R China.
会议名称：
The 5th International Conference of Molecular Simulations and Applied Informatics Technologies(第五届国际分子模拟与信息技术应用学术会议 ICMS&I)
会议时间：
2010-09-01
会议地点：
武汉
会议论文集名称：
The 5th International Conference of Molecular Simulations and Applied Informatics Technologies(第五届国际分子模拟与信息技术应用学术会议 ICMS&I)论文集
关键词：
Acetyl-CoA carboxylase;Computational simulations;pi-pi Interaction;Resistance mechanism
摘要：
Herbicides targeting grass plastidic acetyl-CoA carboxylase (ACCase, EC 6.4.1.2) are selectively effective against graminicides. The intensive worldwide use of this herbicide family has selected for resistance genes in a number of grass weed species. Recently, the active-site W374C mutation was found to confer multi-drug resistance toward haloxyfop (HF), fenoxaprop (FR), Diclofop (DF), and clodinafop (CF) in A. myosuroides. In order to uncover the resistance mechanism due to W374C mutation, the binding of above-mentioned four herbicides to both wild-type and the mutant-type ACCase was investigated in the current work by molecular docking and molecular dynamics (MD) simulations. The binding free energies were calculated by molecular mechanics-Poisson-Boltzmann surface area (MM/PBSA) method. The calculated binding free energy values for four herbicides were qualitatively consistent with the experimental order of IC 50 values. All the computational model and energetic results indicated that the W374C mutation has great effects on the conformational change of the binding pocket and the ligand-protein interactions. The most significant conformational change was found to be associated with the aromatic amino acid residues, such as Phe377, Tyr161′ and Trp346. As a result, the π-π interaction between the ligand and the residue of Phe377 and Tyr161′, which make important contributions to the binding affinity, was decreased after mutation and the binding affinity for the inhibitors to the mutant-type ACCase was less than that to the wild-type enzyme, which accounts for the molecular basis of herbicidal resistance. The structural role and mechanistic insights obtained from computational simulations will provide a new starting point for the rational design of novel inhibitors to overcome drug resistance associated with W374C mutation. © 2010 Springer-Verlag.
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英文
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Design and syntheses of novel N -(benzothiazol-5-yl)-4,5,6,7-tetrahydro-1 H -isoindole-1,3(2 H)-dione and N -(benzothiazol-5-yl)isoindoline-1,3-dione as potent protoporphyrinogen oxidase inhibitors
作者：
Jiang, Li-Li;Zuo, Yang;Wang, Zhi-Fang;Tan, Yin;Wu, Qiong-You;...
期刊：
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY ,2011年59(11):6172-6179 ISSN：0021-8561
通讯作者：
Xi, Zhen
作者机构：
[Yang, Guang-Fu; Wu, Qiong-You; Jiang, Li-Li; Zuo, Yang; Wang, Zhi-Fang; Tan, Yin] Cent China Normal Univ, Coll Chem, Minist Educ, Key Lab Pesticide & Chem Biol, Wuhan 430079, Peoples R China.;[Xi, Zhen] Nankai Univ, State Key Lab Elementoorgan Chem, Tianjin 300071, Peoples R China.
通讯机构：
[Xi, Zhen] N;Nankai Univ, State Key Lab Elementoorgan Chem, Tianjin 300071, Peoples R China.
关键词：
protoporphyrinogen oxidase;4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;isoindoline-1,3-dione;benzothiazole;herbicide
摘要：
Discovery of protoporphyrinogen oxidase (PPO, EC 1.3.3.4) inhibitors has been one of the hottest research areas in the field of herbicide development for many years. As a continuation of our research work on the development of new PPO-inhibiting herbicides, a series of novel N-(benzothiazol-5-yl)-4,5,6,7- tetrahydro-1H-isoindole-1,3(2H)-diones (1a-p) and N-(benzothiazol-5-yl) isoindoline-1,3-diones (2a-h) were designed and synthesized according to the ring-closing strategy of two ortho-substituents. The bioassay results indicated that some newly synthesized compounds exhibited higher PPO inhibition activity than the control of sulfentrazone. Compound 1a, S-(5-(1,3-dioxo-4,5,6,7- tetrahydro-1H-isoindol-2(3H)-yl)-6-fluorobenzothiazol-2-yl) O-methyl carbonothioate, was identified as the most potent inhibitor with k<inf>i</inf> value of 0.08 μM, about 9 times higher than that of sulfentrazone (k <inf>i</inf> = 0.72 μM). Further green house assay showed that compound 1b, methyl 2-((5-(1,3-dioxo-4,5,6,7-tetrahydro-1H-isoindol-2(3H)-yl)-6- fluorobenzothiazol-2-yl)thio)acetate, exhibited herbicidal activity comparable to that of sulfentrazone even at a concentration of 37.5 g ai/ha. In addition, among six tested crops, wheat exhibited high tolerance to compound 1b even at a dosage of 300 g ai/ha. These results indicated that compound 1b might have the potential to be developed as a new herbicide for weed control of wheat field. ©2011 American Chemical Society.
语种：
英文
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Protoporphyrinogen oxidase inhibitor: An ideal target for herbicide discovery
作者：
Hao, Ge-Fei;Zuo, Yang;Yang, Sheng-Gang;Yang, Guang-Fu
* （ 期刊：
CHIMIA ,2011年65(12):961-969 ISSN：0009-4293
通讯作者：
Yang, Guang-Fu
作者机构：
[Yang, Guang-Fu] Cent China Normal Univ, Coll Chem, Key Lab Pesticide & Chem Biol, Minist Educ, Wuhan 430079, Peoples R China.
通讯机构：
[Yang, Guang-Fu] C;Cent China Normal Univ, Coll Chem, Key Lab Pesticide & Chem Biol, Minist Educ, Wuhan 430079, Peoples R China.
关键词：
Herbicide;Inhibitor;Molecular design;Protoporphyrinogen oxidase;QSAR
摘要：
As the last common enzyme in the biosynthetic pathway leading to heme and chlorophyll, protoporphyrinogen oxidase (PPO; EC 1.3.3.4) is an ideal target for herbicide development. Currently, about 30 PPO inhibitors have been developed as agricultural herbicides. PPO inhibitors have displayed environmentally benign, but advantageous characteristics, including low toxicity, low effective concentration, broad herbicidal spectrum (active against both monocotyledon and dicotyledon weeds), quick onset of action, and long lasting effect. Over the last several years, great achievements have been made in revealing the structural biology of PPO. Five PPO crystal structures, four isolated in enzyme-inhibitor complexes and one in the native form, have been determined, including those from Nicotiana tabacum, Myxococcus Xanthus, Bacillus subtilis, and human. Although PPO inhibitors have been developed for over forty years, we continue to uncover exciting future prospects for novel PPO-inhibiting herbicides. In this review, we have summarized the structures of PPOs from plants, human, and bacteria; the interactions between PPOs and inhibitors; the quantitative structure-activity relationships of PPO inhibitors; and the molecular design of new PPO inhibitors. © Schweizerische Chemische Gesellschaft.
语种：
英文
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Structural insight into human variegate porphyria disease
作者：
Qin, Xiaohong;Tan, Ying;Wang, Lele;Wang, Zhifang;Wang, Baifan;...
期刊：
FASEB JOURNAL ,2011年25(2):653-664 ISSN：0892-6638
通讯作者：
Shen, Yuequan
作者机构：
[Qin, Xiaohong; Shen, Yuequan; Wang, Lele] Nankai Univ, Coll Life Sci, Tianjin 300071, Peoples R China.;[Wang, Baifan; Xi, Zhen; Wen, Xin; Tan, Ying; Wang, Zhifang] Nankai Univ, State Key Lab Elementoorgan Chem, Dept Biol Chem, Coll Chem, Tianjin 300071, Peoples R China.;[Yang, Guangfu; Tan, Ying] Cent China Normal Univ, Key Lab Pesticide & Chem Biol, Minist Educ, Coll Chem, Wuhan, Peoples R China.
通讯机构：
[Shen, Yuequan] N;Nankai Univ, Coll Life Sci, Tianjin 300071, Peoples R China.
关键词：
protoporphyrinogen IX oxidase;mitochondrial inner membrane protein;VP-causing mutations;FAD-containing enzyme
摘要：
Human protoporphyrinogen IX oxidase (hPPO), a mitochondrial inner membrane protein, converts protoporphyrinogen IX to protoporphyrin IX in the heme biosynthetic pathway. Mutations in the hPPO gene cause the inherited human disease varie-gate porphyria (VP). In this study, we report the crystal structure of hPPO in complex with the coenzyme flavin adenine dinucleotide (FAD) and the inhibitor acifluorfen at a resolution of 1.9 Å. The structural and biochemical analyses revealed the molecular details of FAD and acifluorfen binding to hPPO as well as the interactions of the substrate with hPPO. Structural analysis and gel chromatography indicated that hPPO is a monomer rather than a homodimer in vitro. The founder-effect mutation R59W in VP patients is most likely caused by a severe electrostatic hindrance in the hydrophilic binding pocket involving the bulky, hydrophobic indolyl ring of the tryptophan. Forty-seven VP-causing mutations were purified by chromatography and kinetically characterized in vitro. The effect of each mutation was demonstrated in the high-resolution crystal structure. © FASEB.
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英文
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Structure-activity relationships of diphenyl-ether as protoporphyrinogen oxidase inhibitors: insights from computational simulations
作者：
Hao, Ge-Fei;Tan, Ying;Yu, Ning-Xi;Yang, Guang-Fu
* （ 期刊：
Journal of Computer-Aided Molecular Design ,2011年25(3):213-222 ISSN：0920-654X
通讯作者：
Yang, Guang-Fu
作者机构：
[Yang, Guang-Fu; Yu, Ning-Xi; Tan, Ying; Hao, Ge-Fei] Cent China Normal Univ, Key Lab Pesticide & Chem Biol, Minist Educ, Coll Chem, Wuhan 430079, Hubei, Peoples R China.;[Yang, Guang-Fu] Cent China Normal Univ, Key Lab Pesticide & Chem Biol, Minist Educ, Coll Chem, 152 Luoyu Rd, Wuhan 430079, Hubei, Peoples R China.
通讯机构：
[Yang, Guang-Fu] C;Cent China Normal Univ, Key Lab Pesticide & Chem Biol, Minist Educ, Coll Chem, 152 Luoyu Rd, Wuhan 430079, Hubei, Peoples R China.
关键词：
Protoporphyrinogen oxidase;Diphenyl-ether inhibitor;Molecular dynamics simulations;Structure-activity relationship
摘要：
Protoporphyrinogen oxidase (PPO, EC 1.3.3.4), which has been identified as a significant target for a great family of herbicides with diverse chemical structures, is the last common enzyme responsible for the seventh step in the biosynthetic pathway to heme and chlorophyll. Among the existing PPO inhibitors, diphenyl-ether is the first commercial family of PPO inhibitors and used as agriculture herbicides for decades. Most importantly, diphenylether inhibitors have been found recently to possess the potential in Photodynamic therapy (PDT) to treat cancer. Herein, molecular dynamics simulations, approximate free energy calculations and hydrogen bond energy calculations were integrated together to uncover the structure-activity relationships of this type of PPO inhibitors. The calculated binding free energies are correlated very well with the values derived from the experimental ki data. According to the established computational models and the results of approximate free energy calculation, the substitution effects at different position were rationalized from the view of binding free energy. Some outlier (e.g. LS) in traditional QSAR study can also be explained reasonably. In addition, the hydrogen bond energy calculation and interaction analysis results indicated that the carbonyl oxygen on position-9 and the NO2 group at position-8 are both vital for the electrostatic interaction with Arg98, which made a great contribution to the binding free energy. These insights from computational simulations are not only helpful for understanding the molecular mechanism of PPO-inhibitor interactions, but also beneficial to the future rational design of novel promising PPO inhibitors. © Springer Science+Business Media B.V. 2011.
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英文
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Design, syntheses, and kinetic evaluation of 3-(phenylamino)oxazolidine-2,4-diones as potent cytochrome bc1 complex inhibitors
作者：
Wang, Fu;Li, Hui;Wang, Le;Yang, Wen-Chao;Wu, Jia-Wei* ;...
期刊：
Bioorganic & Medicinal Chemistry ,2011年19(15):4608-4615 ISSN：0968-0896
通讯作者：
Wu, Jia-Wei
作者机构：
[Yang, Guang-Fu; Wang, Fu; Yang, Wen-Chao; Wu, Jia-Wei; Li, Hui] Cent China Normal Univ, Key Lab Pesticide & Chem Biol, Minist Educ, Coll Chem, Wuhan 430079, Peoples R China.;[Wu, Jia-Wei; Wang, Le] Tsinghua Univ, Dept Biol Sci & Biotechnol, MOE Key Lab Bioinformat, Beijing 100084, Peoples R China.
通讯机构：
[Wu, Jia-Wei] C;Cent China Normal Univ, Key Lab Pesticide & Chem Biol, Minist Educ, Coll Chem, Wuhan 430079, Peoples R China.
关键词：
Oxazolidinedione;Cytochrome bc(1) complex;Famoxadone
摘要：
The cytochrome bc1 complex (EC 1.10.2.2, bc1) is one of the most promising targets for new drugs and agricultural fungicides. Among the existing bc1 complex inhibitors specifically binding to the Qo site, oxazolidinedione derivatives have attracted great attention. With the aim to understand the substituent effects of oxazolidinedione derivatives on the inhibition activity against the bc1 complex, a series of new oxazolidinedione derivatives were designed, synthesized, and biologically evaluated. The further inhibitory kinetics studies against porcine succinate-cytochrome c reductase (SCR) revealed that the representative compound 8d and famoxadone are both non-competitive inhibitors with respect to the substrate cytochrome c, but competitive inhibitors with respect to substrate decylubiquinol (DBH2). In addition, compound 8d and famoxadone showed, respectively, 35-fold and 15-fold greater inhibitory activity against the porcine SCR than the porcine bc1 complex, indicating that these two inhibitors not only inhibited the activity of the bc1 complex, but possibly affect the interaction between the complex II and the bc 1 complex. To our knowledge, this is the first report that famoxadone and its analogs have effects on the interaction between the complex II and the bc1 complex. © 2011 Elsevier Ltd. All rights reserved.
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英文
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